Myocardial ischemias are defined as an imbalance between oxygen needs and supply. This imbalance leads to a disorder of cardiac function. In the vast majority of cases, myocardial ischemias are caused by an insufficiency of blood circulation to the heart muscle tissue, thus depriving the myocardial cells of their oxygen supply or drastically decreasing said supply. These ischemias may be due to obstruction of a vessel (thrombosis), reduction of the inside diameter of an artery (stenosis), or a decrease in coronary blood flow (hypoperfusion) such as in states of circulatory failure associated with severe sepsis with endotoxemic shock. In this connection, it should be noted that severe sepsis also leads to hemodynamic dysfunction with direct myocardial depression. At present, however, it is not clear which mechanism is predominant in reduction of myocardial function, hypoperfusion or myocardial depression by circulating cytokines.
Infarction is one of the major consequences of ischemias. The term infarction describes a localized area of tissue necrosis. Thus, myocardial infarction leads to destruction of a portion of the heart owing to the death of cells of the heart muscle. Myocardial infarction is a very common event. For example, it is estimated that, in France, about 180 000 to 200 000 persons per year, predominantly men, are affected by this disease. It occurs in particular in subjects having cardiovascular risk factors such as use of tobacco, obesity, diabetes, hyperlipidemia or arterial hypertension. The extent of myocardial infarction is a determining element for contractile functional recovery of the myocardium and patients' long-term prognosis.
Acute myocardial infarction (AMI) constitutes an absolute cardiological emergency which requires management by specialized medical and hospital services with treatment of the acute phase with the aim of reperfusing the ischemic heart muscle and of preventing and/or limiting the possible complications associated with infarction that frequently lead to patient death in the first hours or the first days.
Reperfusion is defined as the reestablishment of adequate blood circulation within an ischemic tissue, so that a balance can be achieved again between oxygen needs and supply. Reperfusion in the case of complete interruption of coronary blood flow is generally carried out by clearing the occluded artery.
Although reperfusion undoubtedly protects myocardial cells against cell death caused by persistence of ischemia, it is also accompanied by adverse effects on contractile function (myocardial stunning), cardiac rhythm (occurrence of arrhythmias) and tissue perfusion (“no-reflow”). Recent data even indicate that reperfusion can also, paradoxically, kill some of the reperfused cells (reperfusion necrosis).
During reperfusion of myocardial infarction, drugs belonging to various therapeutic classes, for example antiplatelet agents such as acetylsalicylic acid, beta-blockers, converting enzyme inhibitors (CEIs) or statins have a beneficial effect on patients' prognosis. However, none of these drugs or other drugs currently available, administered during reperfusion, is able to limit the size of the myocardial infarct.
An ischemic situation can also lead to a change of normal function of other organs such as the kidney (Zhao, Jing; Dong, et al. Guoji Bingli Kexue Yu Linchuang Zazhi (2007), 27(6), 539-544) or the brain (Zhu, Xia-Ling, Neuroscience Letters, 2009).
Moreover, amino derivatives of dihydro-1,3,5-triazine of the following general formula (I) are known from European patent EP 1 250 328:

It was demonstrated that these compounds display antidiabetic activity in an experimental model of noninsulin-dependent diabetes, induced in rats by streptozotocin.
The present invention results from the unexpected demonstration, by the inventors, that the amino derivatives of dihydro-1,3,5-triazine of formula (I) make it possible to improve the treatment and/or prevention of diseases associated with ischemia and/or reperfusion, notably cardiac and renal complications. More particularly, it was demonstrated that the compound E 008 made it possible to reduce the production of ROS by complex I of the respiratory chain of endothelial cells, by inhibiting reverse electron flow. Moreover, this compound can prevent loss of mitochondrial membrane potential and can reduce the opening of the mitochondrial permeability transition pore (PTP), notably during ischemia and/or reperfusion events.
The present invention thus relates to a compound of general formula (I):

in which:
R1, R2, R3, and R4 are selected independently from the groups:                —H,        alkyl (C1-C20) unsubstituted, or substituted with halogen, alkyl (C1-C5), alkoxy (C1-C5), cycloalkyl (C3-C8), alkenyl (C2-C20) unsubstituted, or substituted with halogen, alkyl (C1-C5), alkoxy (C1-C5), alkyne (C2-C20) unsubstituted, or substituted with halogen, alkyl (C1-C5), alkoxy (C1-C5),        cycloalkyl (C3-C8) unsubstituted, or substituted with alkyl (C1-C5), alkoxy (C1-C5),        heterocycloalkyl (C3-C8) bearing one or more heteroatoms selected from N, O, S and unsubstituted, or substituted with alkyl (C1-C5), alkoxy (C1-C5),        aryl (C6-C14) alkyl (C1-C20) unsubstituted, or substituted with amino, hydroxy, thio, halogen, alkyl (C1-C5), alkoxy (C1-C5), alkylthio (C1-C5), alkylamino (C1-C5), aryl (C6-C14) oxy, aryl (C6-C14) alkoxy (C1-C5), cyano, trifluoromethyl, carboxy, carboxymethyl or carboxyethyl,        aryl (C6-C14) unsubstituted, or substituted with amino, hydroxy, thio, halogen, alkyl (C1-C5), alkoxy (C1-C5), alkylthio (C1-C5), alkylamino (C1-C5), aryl (C6-C14) oxy, aryl (C6-C14) alkoxy (C1-C5), cyano, trifluoromethyl, carboxy, carboxymethyl or carboxyethyl,        heteroaryl (C1-C13) bearing one or more heteroatoms selected from N, O, S and unsubstituted, or substituted with amino, hydroxy, thio, halogen, alkyl (C1-C5), alkoxy (C1-C5), alkylthio (C1-C5), alkylamino (C1-C5), aryl (C6-C14) oxy, aryl (C6-C14) alkoxy (C1-C5), cyano, trifluoromethyl, carboxy, carboxymethyl or carboxyethyl,        
R1 and R2, on the one hand, and R3 and R4, on the other hand, which can form, with the nitrogen atom, a ring with n ring members (n between 3 and 8) comprising or not comprising one or more heteroatoms selected from N, O, S and which can be substituted with one or more of the following groups: amino, hydroxy, thio, halogen, alkyl (C1-C5), alkoxy (C1-C5), alkylthio (C1-C5), alkylamino (C1-C5), aryl (C6-C14) oxy, aryl (C6-C14) alkoxy (C1-C5), cyano, trifluoromethyl, carboxy, carboxymethyl or carboxyethyl,
R5 and R6 are selected independently from the groups:                H,        alkyl (C1-C20) unsubstituted, or substituted with amino, hydroxy, thio, halogen, alkyl (C1-C5), alkoxy (C1-C5), alkylthio (C1-C5), alkylamino (C1-C5), aryl (C6-C14) oxy, aryl (C6-C14) alkoxy (C1-C5), cyano, trifluoromethyl, carboxy, carboxymethyl or carboxyethyl,        alkenyl (C2-C20) unsubstituted, or substituted with amino, hydroxy, thio, halogen, alkyl (C1-C5), alkoxy (C1-C5), alkylthio (C1-C5), alkylamino (C1-C5), aryl (C6-C14) oxy, aryl (C6-C14) alkoxy (C1-C5), cyano, trifluoromethyl, carboxy, carboxymethyl or carboxyethyl,        alkynyl (C2-C20) unsubstituted, or substituted with amino, hydroxy, thio, halogen, alkyl (C1-C5), alkoxy (C1-C5), alkylthio (C1-C5), alkylamino (C1-C5), aryl (C6-C14) oxy, aryl (C6-C14) alkoxy (C1-C5), cyano, trifluoromethyl, carboxy, carboxymethyl or carboxyethyl,        cycloalkyl (C3-C8) unsubstituted, or substituted with amino, hydroxy, thio, halogen, alkyl (C1-C5), alkoxy (C1-C5), alkylthio (C1-C5), alkylamino (C1-C5), aryl (C6-C14) oxy, aryl (C6-C14) alkoxy (C1-C5), cyano, trifluoromethyl, carboxy, carboxymethyl or carboxyethyl,        heterocycloalkyl (C3-C8) bearing one or more heteroatoms selected from N, O, S and unsubstituted, or substituted with amino, hydroxy, thio, halogen, alkyl (C1-C5), alkoxy (C1-C5), alkylthio (C1-C5), alkylamino (C1-C5), aryl (C6-C14) oxy, aryl (C6-C14) alkoxy (C1-C5), cyano, trifluoromethyl, carboxy, carboxymethyl or carboxyethyl,        aryl (C6-C14) unsubstituted, or substituted with amino, hydroxy, thio, halogen, alkyl (C1-C5), alkoxy (C1-C5), alkylthio (C1-C5), alkylamino (C1-C5), aryl (C6-C14) oxy, aryl (C6-C14) alkoxy (C1-C5), cyano, trifluoromethyl, carboxy, carboxymethyl or carboxyethyl,        heteroaryl (C1-C13) bearing one or more heteroatoms selected from N, O, S and unsubstituted, or substituted with amino, hydroxy, thio, halogen, alkyl (C1-C5), alkoxy (C1-C5), alkylthio (C1-C5), alkylamino (C1-C5), aryl (C6-C14) oxy, aryl (C6-C14) alkoxy (C1-C5), cyano, trifluoromethyl, carboxy, carboxymethyl or carboxyethyl,        aryl (C6-C14) alkyl (C1-C5) unsubstituted, or substituted with amino, hydroxy, thio, halogen, alkyl (C1-C5), alkoxy (C1-C5), alkylthio (C1-C5), alkylamino (C1-C5), aryl (C6-C14) oxy, aryl (C6-C14) alkoxy (C1-C5), cyano, trifluoromethyl, carboxy, carboxymethyl or carboxyethyl,        
and R5 and R6 can form, with the carbon atom to which they are attached, a ring with m ring members (m between 3 and 8) comprising or not comprising one or more heteroatoms selected from N, O, S and which can be substituted with amino, hydroxy, thio, halogen, alkyl (C1-C5), alkoxy (C1-C5), alkylthio (C1-C5), alkylamino (C1-C5), aryl (C6-C14) oxy, aryl (C6-C14) alkoxy (C1-C5), cyano, trifluoromethyl, carboxy, carboxymethyl or carboxyethyl,
or which can form, with the carbon atom, a C10-C30 polycyclic residue unsubstituted, or substituted with amino, hydroxy, thio, halogen, alkyl (C1-C5), alkoxy (C1-C5), alkylthio (C1-C5), alkylamino (C1-C5), aryl (C6-C14) oxy, aryl (C6-C14) alkoxy (C1-C5), cyano, trifluoromethyl, carboxy, carboxymethyl or carboxyethyl,
and R5 and R6 can also represent together the group ═O or ═S,
moreover the nitrogen atom of a heterocycloalkyl or heteroaryl group can be substituted with an alkyl (C1-C5), cycloalkyl (C3-C8), aryl (C6-C14), aryl (C6-C14) alkyl (C1-C5) or acyl (C1-C6) group,
as well as the tautomeric, enantiomeric, diastereoisomeric and epimeric forms and the pharmaceutically acceptable salts,
for use in the treatment and/or prevention of lesions, disorders or diseases associated with ischemia and/or reperfusion.
The present invention also relates to the use of a compound of formula (I) as defined above, for preparing a drug intended for the prevention and/or treatment of a lesion, a disorder or a disease associated with ischemia and/or reperfusion.
The present invention also relates to a method of prevention and/or treatment of a pathology associated with ischemia and/or reperfusion in a patient, in which a prophylactically or therapeutically effective amount of a compound of formula (I) as defined above is administered to said patient.